Interactive Association of Five Candidate Polymorphisms in Apelin/APJ Pathway with Coronary Artery Disease among Chinese Hypertensive Patients

Abstract

BackgroundVia sequencing the genes of apelin/angiotensin receptor-like 1 (apelin/APJ) pathway, we have recently identified and validated four common polymorphisms (rs3761581, rs56204867, rs7119375, and rs10501367) implicated in the development of hypertension. Extending these findings, we, in Chinese hypertensive patients, sought to investigate the association of these four polymorphisms and one additional promising candidate (rs9943582) from this pathway with the risk of developing coronary artery disease (CAD).Methodology/Principal FindingsGenotypes were obtained from 994 sporadic CAD patients and 708 age- and sex-matched controls. All participants were hypertensives and angiographically-confirmed. Data were analyzed by Haplo.Stats and multifactor dimensionality reduction (MDR) softwares. Genotype distributions of five examined polymorphisms satisfied Hardy-Weinberg equilibrium in controls of both genders. Single-locus analyses exhibited no significant differences in the genotype/allele frequencies of examined polymorphisms between CAD patients and controls (P>0.05), even after controlling traditional cardiovascular confounders. In haplotype analyses, low-penetrance haplotype G-A (in order of rs56204867 and rs3761581 from apelin gene) was significantly overrepresented in controls (1.73%) relative to in CAD patients (0.4%) in males (P = 0.047). Further interaction analyses suggested an overall best MDR model including rs3761581 in males (P = 0.0408) and including rs7119375 and rs9943582 in females (P<0.0001), which were further substantiated in the classical logistical regression model.ConclusionsOur findings demonstrated a contributive role of low-penetrance haplotype in apelin gene on CAD in males, and more importantly, interactive effects of genetic defects in apelin/APJ pathway might confer a potential risk in Chinese hypertensive patients.

MicroRNA-765 influences arterial stiffness through modulating apelin expression

“…Therefore, the genetic effects might differ when it expressed in different cell types. The sex-specific effect of apelin had been documented in other human studies (Ba et al, 2014;Jin et al, 2012). Similar to ours, a study investigating Chinese obese children showed that the correlation between serum aplein levels and obesity-related biomarkers was only observed in girls, but not in boys (Ba et al, 2014).…”

Genetic differences and aberrant methylation in the apelin system predict the risk of high-altitude pulmonary edema

“…However, the genetic and epigenetic regulations of apelin signaling have not been investigated in HAPE and HA adaptation, even though variants of the genes involved in this signaling have been extensively investigated in several disease conditions (17)(18)(19)(20)(21)(22)(23)(24). Our previous reports on NOS3 revealed a selection of polymorphisms in both HA adaptation and HAPE (17,18).…”

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

“…A striking example is provided by one of the first discovered smORFs, apelin. Since its change in annotation from lncRNA to mRNA following its incidental discovery and functional characterization, genomic studies have identified polymorphisms linked to cardiovascular diseases and obesity risks (Zhao et al 2010;Liao et al 2011;Jin et al 2012;Sentinelli et al 2016). Finally, many published studies may need to be re-interpreted in light of the existence of more than one CDS per mRNA, and future overexpression and knockdown experiments will become technically more complex.…”